3-mercuric-2-methoxy-1-succinimidopropane derivatives



United States Patent 3-MERCURIC-2-METHOXY-1-SUCCINI1VHDO- PRQPANE DERIVATIVES Kai Arne Jensen, Copenhagen, and Carl Lund Jensen, Holte, Denmark, assignors to Aktieselskabet Ferrosan, Copenhagen, Denmark, a firm No Drawing. Application April 27, 1956 Serial No. 580,985

Claims priority, application Denmark August 22, 1955 5 Claims. (til. 260--242) This invention relates to 3-mercuric-2-inethoxy-l-succinimidopropane derivatives and to processes for their preparation.

The principal object of the invention is to prepare a series of compounds of this nature having the valuable pharmacological property of being diuretics.

The compounds of the invention may be represented either by the formula:

in which X is an acid residue, or by the formula:

GE -O 0 0611 CHr-C 0 (II) wherein HY represents a purine compound.

It will be seen that these formulae represent closely related products, if an intermediate product is assumed, corresponding to Formula I with X representing a hydroxyl group. With an acid this would give the salts of Formula I whereas a purine compound is added in complex linkage to the mercury atom.

In the preferred manner of preparing the compounds of the invention, 3-acetoxy-mercuric-2-methoxy-1-succinimidopropane is first produced by reacting allyl succinimide with mercuric acetate in boiling methanol.

If another acid residue is desired, the acetoxy compound is further reacted with a salt containing the desired acid residue or with the acid in question. In this manner the acetoxy group can for example be replaced by chlorine.

If a purine addition complex is desired, the purine compound in question is admixed to the acetoxy compound or to the reaction mixture containing the latter, whereafter the mixture is refluxed until the reaction has taken place, usually in the course of 2 to 4 hours.

The preferred purine compound is theophylline, but others may be used, such as caifeine and theobromine.

The compounds of the invention are white crystalline substances which are soluble in water, sparingly soluble in methanol and in acetone, and substantially insoluble in ether and in benzene.

By oral administration, the compounds of the invention give an increased diuresis as compared with a known Hg-diuretic in equitoxical doses.

This was proved by the following investigations, in which the theophylline compound of the invention (A) was compared with 3-chloro-mercuric-Z-methoxypropyl carbamide (B).

TOXICITY Acute toxicity in mice and rats by peroral administration was determined. The following values for LD 50 in mg. Hg per kg. body weight were found:

Z,hb0,136

Patented Nov. 11, 195% Table 1 Compound Mice, Rats,

rug/kg. rug/kg.

The toxicity of A is thus 50 to 70 percent over that of B.

DIURETIC EFFECT The diuretic effect was determined by comparing the urine production of rats after peroral administration of compounds A and B, respectively, with the urine production of controls. Each group numbered 4 rats. The diuretics were administered in equitoxical doses, i. e. 7 mg. Hg/kg. body weight of compound A and 10 mg. -l-lg/kg. of compound B. The results appear from the following table.

it appears from the table that the compound of the invention (compound A) compares favorably with the known compound in diuretic effect.

Both compounds were further tested by intravenous administration to anesthetized rabbits with catheters operatively inserted in the bladder through the abdominal wall. The diureses were measured during equal periods before and after administration of the diuretics with the following results.

Table 3 Diuresis in mi. Increase of diuresis is- Compound Dose Before After ml. Perinjection injection cent 7 65 58 330 9 57 48 30 1 15 62 47 310 A 15 12s 11;; 7520 23 58 36 29 87 58 200 15 9 1:30 B 3 n /1n....{ 22

Here too the compound of the invention shows the better effect.

Histological investigations of rats have shown that neither compound A nor compound B causes any noticeable damage to the organs even by daily administrations in therapeutic doses for a month. Only small changes sponding to 40 mg. Hg.

was 81 percent, whereby 6 patients showed less than.

are noted in the kidney tissues, a comparison being slightly in favor of compound A.

Clinical investigations have also been made. Thus, 10 patients with edema were given compound A orally with the following results:

In 4 patients a questionable increase of diuresis was noted, in 2 patients a moderate increase occurred, and 4 patients had a pronounced increase. The average increase in the diuresis for all 10 patients was 65 percent.

In another investigation 4 patients with heart insufficiency and edemas were given compound A in daily doses of 20, 20, 30 and 10 mg. Hg, respectively, with the results of increased diuresis and weight losses of 2.2 kg. (in 4 days), 4.5 kg. (in 11 days), 5.5 kg. (in 5 days) and 1 kg. (in 5 days), respectively.

A third investigation was carried out as follows. 16 patients were given compound A in daily doses corre- The average increase in diuresis 35 percent increase, 4 patients showed 35 to 100 percent increase, and 6 patients showed more than 100 percent increase.

The average weight loss for 12 patients in the observation period was 1.8 kg.

Two of the patients had slight nausea, and two had severe nausea, vomiting and diarrhea, but no really serious secondary effects were noticed.

In a fourth investigation, the daily doses of compound A were corresponding to 60 mg. Hg. 14 patients were involved, and the average increase in diuresis was 131 percent.

2 patients showed less than 35 percent increase, 5 patients showed 35 to 100 percent increase, and 7 patients showed more than 100 percent increase.

Secondary eifects were noted in 3 patients getting nausea, vomiting and diarrhea.

The average weight loss for all 14 patients during the observation period was 2.9 kg.

As will be seen from the preceding description the compounds of the invention are preferably administered orally. A convenient dosage unit corresponds to 10 mg. Hg, and a daily dose for adults preferably corresponds to from 0.1 to 1 mg. Hg per kg. body weight.

A preferred dosage unit form is a tablet containing a compound of the invention in a proportion corresponding to a content of 10 mg. of mercury, and the preferred compound is the theophylline compound.

The following non-limitative examples illustrate the preparation of the compounds of the invention.

EXAMPLE 1 14 g. of allyl succinimide and 32 g. of mercuric acetate in 120 ccs. of methanol were refluxed for 8 hours, whereafter the reaction mixture was evaporated in vacuum to a syrupy consistency. The residue was dissolved in 150 ccs. of methanol, 20 g. of theophylline were added, and the mixture was refluxed for 3 hours, filtered and then cooled to -l0 C. After standing for 24 hours, the precipitate was filtered off and re-crystallized from methanol, yielding 24 g. of 3-mercuric-2-methoxy-l-succinimidopropane, theophylline with M. P. C.

By re-crystallization from acetone, modifications can be obtained melting at 146 C. and 192 C., respectively, due to loss of water from the complex.

EXAMPLE 2 wherein X denotes an acid residue selected from the group consisting of chlorine and acetoxy, and

wherein HY denotes a purine compound selected from the group consisting of theophylline, caffeine, and theobromine.

2. Theophylline 3-hydroxymercuric-2-methoxy-1-succinimidopropane.

3. 3 acetoxymercuric 2 methoxy l-succinimidopropane.

4. 3-chloromercuric-2-methoxyl-l-succinimidopropane.

5. In a process for the production of 3-mercuric-2- methoxy-1-succinimidopropane derivatives, the step of refluxing allyl succinimide with mercuric acetate in methanolic solution to form a reaction mixture and heating the reaction mixture with theophylline.

References Cited in the file of this patent UNITED STATES PATENTS 2,635,982 Rowland Apr. 21, 1953 

1. 3-MERCURIC-2-METHOXY-1-SUCCINIMIDPROPANE DERIVATIVES SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS OF THE FORMULAE: 